The general goal of this project is to develop novel HIV immunogens and adjuvant formulations as preventive HIV vaccines. This project will build on prior work of development of peptide immunogens for HIV and mapping immunogenic HIV protein epitopes, combined with new expertise in RNA mimetope selection and RNA-protein interactions, alpha2-macroglobulin biochemistry and basic T cell immunobiology to design and test new HIV peptide and RNA immunogens as well as novel adjuvant formulations. Specific aims are as follows. 1) We have designed a prototype multivalent HIV env peptide immunogen made up of 4 hybrid peptides each with T helper (Th), B cell neutralizing (B) and MHC Class I-restricted CTL (Tc). We will test the multivalent HIV env peptide immunogen formulated with alpha2-macroglobulin (alpha2M) in immunogenicity studies in mice and rhesus monkeys. Alpha2M is an bundant serum protein with the capacity for irreversibly capturing diverse proteins for rapid delivery into antigen presenting cells via the alpha2M receptor. 2) We use mabs and polyclonal sera against gp160 neutralizing sites to select single- stranded RNA oligonucleotides that bind to the V regions of the antibodies and mimic the secondary and higher order structures of neutralizing determinants of gp160 env. High affinity-binding oligonucleotides will be selected and tested for their ability to serve as immunogens in mice and rhesus monkeys to induce broadly-cross reactive anti-HIV neutralizing antibodies. 3) We will formulate T1-SP10 (A) multivalent HIV env peptide immunogen with various combinations of molecules that will stimulate T cell CD 28 and B cell CD40 molecules in concert with T cell receptor (TCR) triggering to expand memory T and B cell induction and serve as novel adjuvant formulations for HIV subunit immunogens. This, these studies will combine new technologies with prior work on HIV vaccine development to solve existing problems and move HIV vaccine development forward.